tbuckley/cabot-search huggingface dataset:
T021: Radiation-Free Therapy as the INitial treatment of Good-prognosis early non-bulky Hodgkin lymphoma, defined by a low Metabolic Tumor Volume and a negative PET-2 - RAFTING Trial.
Authors: Andrea Gallamini, Marco Picardi, Kateryna Filonenko, Manuel Gotti, Javier Núñez Céspedes, Andrea Rossi, Eva Domingo-Domènech, Agnieszka Giza, Roberto Sorasio, Livio Trentin, Mariana Bastos Oteiro, Ewa Paszkiewicz-Kozik, Ramon García Sanz, Caterina Patti, Stephane Chauvie, Fabrizio Bergesio, Luca Guerra, Alessandro Rambaldi, Ana Sureda Balari, Jan Maciej Zaucha
Journal: HemaSphere (2022)

Figure 1: RAFTING Trial workflow Introduction: The efficacy of combined modality treatment (CMT) with chemotherapy (CT) and radiotherapy (RT) in early-stage Hodgkin Lymphoma (eHL) is offset by long-term morbidity, with a cumulative incidence of Second Primary Malignancy (SPM) at 40 years of 48.5% (Schaapveld 2015). The primary endpoint of the RAFTING trial is a 3-Y PFS ≥ 90% of a RT-free CT (2 or 4 ABVD cycles) in low-risk non-bulky stage I-IIA eHL with a low Metabolic Tumor Volume at baseline (bMTV) and a negative PET-2. Secondary endpoints: (a) Effectiveness of delayed Involved-node RT (In-RT) and Nivolumab maintenance, 240 mg. i.v. twice a month for one year (Nivo-m) in case of "limited" relapse (LR: stage I-II with up to 3 new nodal areas) after CT; (b) effectiveness of the triplet: ABVD x 4, InRT and Nivo-m in high-risk eHL, with either a high bMTV or a positive PET-2; (c) predictive value of tumor cell-free DNA (cfDNA) in detecting an impending relapse during follow-up of patients (p.) in CR after CT alone. Methods: RAFTING is a prospective phase 2 multi-center, international trial, enrolling 160 non-bulky stage I-IIA eHL p. from four European countries. Treatment intensity is tailored to three classes of p. with a different risk of treatment failure, depending on (a) the modified EORTC criteria (m-EORTC), in which classical bulky is taken over by a Large Nodal Mass (LNM, defined by the largest diameter > 5 cm in CT or PET/CT scans), (b) bMTV and (c) PET-2. The risk-stratified treatment is the following: Group 1: PET-2 neg. & low bMTV p, treated with 2–4 ABVD cycles (depending on m-EORTC), addressed, once in CR, to a 3-monthly cfDNA assay; Group 2: group 1 p. relapsing with a LR, treated with delayed INRT at the dose of 36 Gy, and Nivo-m; Group 3: PET-2 positive (Group 3a), and/or a high bMTV (Group 3b) p. treated with ABVD x 4, INRT, (20 or 30 Gy), and Nivo-m. All PET/CT are centrally reviewed. Results: out of 55 p. enrolled 52 were eligible, and 31/52 with both bMTV and PET-2 assessed were stratified for risk as follows: group 1a: 6; group 1b 17; group 3a: 2; Group 3b: 6. Three p. of group 3 are on Nivo-m, without major side effects. Updated results will be presented. Conclusions: (a) the majority of p. enrolled so far (74%) belong to Group 1 (low risk), and most of them (74%) are treated with 4 ABVD because of mEORTC criteria (most often a LNM); (b) Most p. were attributed to Group 3 because of a high bMTV (6/8); (c) Nivo-m is feasible, safe and well-tolerated (no SAE).
P059: Multi-effector cell targeting with half-life extended bispecific scFv in Hodgkin lymphoma
Authors: Zhiyuan Shi, Verena Kern, Max Freihammer, Jennifer Schitz, Sven Borchmann
Journal: HemaSphere (2022)

Immunotherapy has revolutionized the treatment of many hematological cancers. One form of cancer immunotherapy is exploiting immune effector cells, for example, T-cells or NK-cells, by retargeting them to cancer-associated antigens which have been identified and validated for most hematological cancers. However, most strategies to do so employed to date suffer from disadvantages such as unfavorable pharmacokinetics and unspecific immune system activation with current bispecific antibodies, high complexity and cost with CAR T-cells or lack of efficacy with many simple monoclonal antibodies targeting tumor-associated antigens. Thus, it is highly desirable to develop new technologies that can overcome these limitations. Here, we introduce our strategy to retarget various immune effector cells simultaneously with half-life extended bispecific scFv constructs to Hodgkin lymphoma-associated antigens e.g., CD30. In doing so, we target CD3, CD16 and CD28 on immune effector cells. Half-life extension is achieved by fusing the scFv constructs to a repetitive amino acid sequence without secondary structure and immunogenicity developed by us. After optimizing the production of our constructs in mammalian protein production systems we performed functional in vitro validation. Our data shows that the designed bispecific scFv constructs can bind their targets specifically and simultaneously and facilitate the formation of an artificial immunological synapse with immune cells secreting toxic proteins such as perforin and granzymes leading to the apoptosis of the lymphoma cells. We show direct cytotoxicity towards tumor cells in vitro and a target-cell specific release of cytokines such as TNFα and IFNγ by effector cells. We are now moving some constructs into cell line xenograft mouse models for further in vivo validation.
P014: Prognostic significance of nutritional indexes (CONUT and PNI) in classical Hodgkin lymphoma patients
Authors: Rita Costa E. Sousa, Cátia Almeida, Adriana Roque, Maria Carolina Afonso, Dulcelena Neves, Raquel Guilherme, Lenka Ruzickova, José Pedro Carda, Catarina Geraldes, Marília Gomes
Journal: HemaSphere (2022)

Figure 1: ROC curve for PNI in predicting progression-free survival and Overall and progression-free survival according to PNI and CONUT scores. Background: Several recent studies have shown the clinical significance of poor nutritional status accessed by Prognostic Nutritional Index (PNI) and Controlling Nutritional status (CONUT) on patients (pts) with solid and hematological malignancies, but its impact on classical Hodgkin lymphoma (cHL) is not established. Aim: To evaluate the prognostic value of baseline PNI and CONUT in cHL. Methods: Retrospective analysis of adult pts with cHL, diagnosed between 1990 and 2017 and treated with curative intent with ABVD, escalated BEACOPP or ABVD hybrid regimen and with available data on all PNI variables. The cutoff point for PNI was evaluated using ROC statistics. The association between both scores and progression free survival (PFS) and overall survival (OS) was performed by Cox regression. Results: 318pts were included, 46.2% male, with median age of 32 (18–80). Of these, 246 (77.3%) had nodular sclerosis and 213 (67%) had advanced stage cHL (GHSG classification). Information on BMI was available for 187pts (median 23.5kg/m2) and 3.2% had BMI<18.5kg/m2. Mean baseline PNI was 47.2 (SD±8.7) and median PFS of 364 months (m). After ROC statistics, the optimal cutoff for PNI to predict 5-year (y) PFS was 47 (Sensibility 36%, Specificity 47%, AUC 0,377). PNI≥47 was significantly associated with an improved PFS (HR 0.42; p<0.001) in univariate analysis, with PFS 5y of 69% for PNI<47 and 82% for PNI≥47. In advanced stages, PNI≥47 retains its prognostic value, even after adjusting for IPS (HR 0.059; p=0.034). After a median follow-up of 145m, median OS was not reached. PNI≥47 was significantly associated with an improved OS (HR 0.35; p<0.001) in univariate analysis but lost its significance in a multivariate model. CONUT was calculated in 191pts (median follow-up 163m), with a median score of 2 (0–9) and most pts with normal/mild risk (86.9%). Higher values of CONUT were associated with poorer PFS (HR 1.13; p=0.040) and OS (HR 1.26; p=0.001), despite its categorization not being a significant predictor of PFS (HR 1.30; p=0.150). The four categories of CONUT were predictors for OS (HR 2.04; p=0.001). Conclusion: In our cohort, baseline poor nutritional status, calculated with PNI or CONUT, was associated with significantly worse prognosis in cHL. Categorization of CONUT was not a significant predictor of PFS most likely due to a shorter follow-up and fewer pts included. Further external validation of theses scores in cHL is warranted.
P042: Metabolic regulation of adaptive response to arginine deprivation in Hodgkin Lymphoma
Authors: Alessandra Romano, Grazia Scandura, Gabriella Santuccio, Fabrizio Puglisi, Daniela Cambria, Angela Maria Amorini, Enrico La Spina, Nunziatina Laura Parrinello, Cesarina Giallongo, Daniele Tibullo, Claudio Cerchione, Giovanni Martinelli, Giorgia Simonetti, Francesco Di Raimondo
Journal: HemaSphere (2022)

Our group has previously shown an altered aminoacidic homeostasis in the microenvironment of classic Hodgkin`s Lymphoma (HL), due to arginine deprivation, which plays a major role in the immune-escape mechanisms and T-cell anergy induction. To study the metabolic adaptive response to arginine deprivation in vitro, we cultured three HL human cell lines (L428, L540, KMH2) with customized complete media or lacking Arg (R0), supplemented with 10% dialyzed fetal bovine serum, in six independent experiments to collect their global metabolomic analysis by gas chromatography-mass spectrometry (GC/MS) and liquid chromatography-tandem mass spectrometry (LC/MS/MS) platforms by Metabolon Inc and transcriptome profiling by RNA-seq. Apotpostosis and mitochondrial depolarization were measured by FACS. Findings were validated by qRT-PCR and Western Blot analysis. Gene set enrichment analysis (GSEA) showed deep transcriptome rearrangements in KMH2 and HDMYZ cell lines, involving upregulation of genes required for the unfolded protein response, p53 pathway and networks and proteosome degradation, with a minimal effect on metabolism features, except for the genes involved in lactate metabolism. Arg deprivation caused mitochondrial distress and transcriptional reprogramming, via induction of oxidative stress, affecting the mitochondrial activity, switching from glucose-based metabolism to mitochondrial oxidation of fatty acids, requiring the transfer of fatty acids from lipid droplets to mitochondria. RNA-seq analysis showed that induction of ferroptosis key genes GPX4, TXNRD1 and ACSL4 together with reduced intracellular GSH levels and increased amount of cystine and methionine sulfoxide occurred upon arginine deprivation. The low-energy metabolic state induced by the adaptive response to arg-deprivation posed KMH2-HL cells into a quiescence state, with elevated HMOX1 and HMOX-2 to scavenge the excess ROS with subsequent genome instability as shown by increased γHA2X+/ATM+ cells. In HDMYZ, the increased oxidative stress due to arginine deprivation induced the engagement of the UFMylation pathway. These findings were confirmed in vivo, since in peripheral blood of HL patients we found reduced amount of GSH, glutamine and S-adenosylhomocysteine, citrate, methionine (p<0.001), as detected by HPLC. Taken together, our data suggest how arginine deprivation can regulate lipid trafficking, ferroptosis and UFMylation, novel potential targets to overcome drug resistance in cHL.
T082: AVD - a possible golden standard in the first-line treatment of older classical Hodgkin lymphoma patients
Authors: Ninja Övergaard, Kjersti Lia, Peter Asdahl, Per Wikman, Ingrid Glimelius, Ingemar Lagerlöf., Ann-Sofie Johansson, Lotta Hansson, Gunilla Enblad, Johan Linderoth, Christina Goldkuhl, Alexander Fosså, Peter Kamper, Daniel Molin
Journal: HemaSphere (2022)

Figure 1: 5-year overall survival in cHL patients aged ≥60 years treated with curative intent in Sweden, Denmark and Norway 2000–2021. Limited stage disease (top) and advanced stage disease (bottom) stratified by first-line chemotherapy regimen. Background: First-line treatment in patients ≥60 years with classical Hodgkin lymphoma (cHL) is challenging and less well studied compared to younger patients. Although survival has improved over the past decades, older patients still have an inferior outcome and no golden standard in first-line treatment exists. These patients often have a higher comorbidity-burden and are more susceptible to acute toxicity. In addition, the ageing body and an increased incidence of more advanced disease makes curative treatment challenging. Method: We collected patient and treatment data from Sweden, Denmark and Norway for 1554 patients aged ≥60 years at cHL diagnosis who received treatment with curative intent, diagnosed from January 1st, 2000 to December 30th, 2021 from national registries. Data was also collected from patient records. Survival was estimated using Kaplan-Meyer curves and the risk of death was estimated with both univariable and multivariable Cox regression analysis. Patients were grouped according to first-line chemotherapy regimen; ABVD (n=671), AVD (n=122), CHOP (n=465) or "other" (n=296, single agent or combination chemotherapy). Results: Median age was 70 years (60–94 years) for all patients and stages. In the different treatment groups the median age was 66 years (60–90), 74 years (61–86), 73 years (60–92), 73 years (60–94) for ABVD, AVD, CHOP and "other", respectively. Overall survival (OS) at 5 years for limited stage patients was 85% for the ABVD group, 94% for AVD, 64% for CHOP and 48% for patients who received "other" chemotherapy. A majority of limited stage patients also received radiotherapy. In patients with advanced stage disease 5-year OS was 63% in the ABVD group, 64% for AVD, 46% for CHOP and 39% in the "other"-group. In multivariable OS analysis patients treated with CHOP had a significantly poorer outcome than those treated with AVD, while there was no significant difference between AVD and ABVD. The majority of patients receiving AVD were treated in Sweden after 2016 and patients in the CHOP and other-group generally had poorer performance status compared to the ABVD-group. PFS data will be presented. Conclusion: AVD is less toxic than ABVD, as bleomycin is omitted, and outcome with respect to OS was equal to ABVD and superior to CHOP in this patient group. Based on our findings AVD is a preferable treatment and should be considered as backbone in prospective studies with novel drugs.
P009: Improved Overall Survival with First-Line Brentuximab Vedotin plus Chemotherapy in Patients with Advanced Stage III/IV Classical Hodgkin Lymphoma: An Updated Analysis of ECHELON-1
Authors: Martin Hutchings, Stephen M. Ansell, Joseph M. Connors, Won Seog Kim, Andrea Gallamini, Radhakrishnan Ramchandren, Jonathan W. Friedberg, Ranjana Advani, Andrew M. Evens, Piotr Smolewski, Kerry J. Savage, Nancy L. Bartlett, Hyeon-Seok Eom, Jeremy S. Abramson, Cassie Dong, Frank Campana, Keenan Fenton, Markus Puhlmann, David J. Straus, John Radford
Journal: HemaSphere (2022)

Figure 1: Overall Survival in the Intent-to-Treat Population. New first-line treatment strategies for classical Hodgkin lymphoma (cHL) have not improved overall survival (OS) compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Five-year data from ECHELON-1 (NCT01712490) supported long-term progression-free survival (PFS) with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) in patients (pts) with previously untreated stage III/IV cHL vs ABVD, with a manageable long-term safety profile. We report an OS analysis from ECHELON-1 after a median of 6 years of follow-up (data cutoff June 1, 2021). Randomized pts (1:1) received ≤6 cycles of A+AVD (n=664) or ABVD (n=670) on days 1 and 15, every 28 days. The key secondary end point was OS (event-driven, type-1 error controlled) in the intent-to-treat population. Analysis of OS in prespecified subgroups was exploratory and not adjusted for multiplicity. PFS per investigator was reported for long-term follow-up. Deaths during follow-up, including reported causes of death per investigator, were summarized. We observed 39 OS events in the A+AVD arm vs 64 with ABVD, favoring A+AVD (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.40–0.88; p=0.009; median follow-up 73 months; Figure). OS was examined in prespecified subgroups; in a multivariable analysis adjusting for baseline demographic and disease factors, OS benefit was preserved (HR 0.53; 95% CI 0.34–0.83). PFS favored A+AVD (HR 0.68; 95% CI 0.53–0.86), consistent with prior reports. Subsequent therapy use was less frequent with A+AVD vs ABVD (135 [20%] vs 157 [24%]) including fewer autologous (44 [7%] vs 59 [9%]) and allogeneic stem cell transplants (4 [<1%] vs 12 [2%]) while use of radiation was similar (55 [8%] vs 58 [9%]), suggesting that the OS benefit was not due to undertreatment of pts in the ABVD arm. Fewer second malignancies (23 vs 32) and fewer deaths related to cHL or treatment complications (32 vs 45) or to second malignancies (1 vs 11) were reported with A+AVD vs ABVD, respectively; treatment-related deaths were comparable (8 vs 7). While fertility was not formally assessed, a total of 191 pregnancies were reported among pts and their partners (A+AVD 113; ABVD 78). More pts had peripheral neuropathy with A+AVD (443 [67%]) vs ABVD (286 [43%]), but most improved or resolved at last follow-up (379 [86%] vs 249 [87%]). To conclude, A+AVD significantly reduced risk of death vs ABVD by 41%. The long-term safety profile was manageable, consistent with prior reports.
P092: Estimating the dosimetric benefit of involved-node radiotherapy in comparison to involved-field radiotherapy - implications from the GHSG HD 17 trial
Authors: Michael Oertel, Dominik Hering, Nina Nacke, Christopher Kittel, Kai Kröger, Jan Kriz, Michael Fuchs, Christian Baues, Dirk Vordermark, Rita Engenhart-Cabillic, Klaus Herfarth, Peter Lukas, Heinz Schmidberger, Simone Marnitz, Peter Borchmann, Andreas Engert, Uwe Haverkamp, Hans Theodor Eich
Journal: HemaSphere (2022)

Table 1: Size of the planning targe volume (PTV) and dose exposure to organs at risks in comparison between involved-field (IFRT) radiotherapy and involved-node radiotherapy (INRT). Gy: Gray Question: The HD17 trial of the German Hodgkin Study Group evaluated the value of consolidative involved-node (IN)RT for patients with PET-positivity after chemotherapy and enabled a comparison between INRT and involved-field (IF)RT [1]. The present work analyzes the organs at risk (OAR) exposure of the performed RT. Methods/Material: For dosimetric evaluation, all INRT-plans in the HD 17 trial were requested and compared to a random selection of IFRT-cases in the standard arm. Dose-volume histograms (DVH), either paper-based or digital, were analyzed using SPSS (version 28, IBM, Armonk, NY, USA). For comparisons between the two RT concepts, a two-sided t-test or a Mann-Whitney U test was used with a p-value < 0.05 considered as significant. Results: In total, 148 DVH (INRT: 112, IFRT: 36) could be evaluated. Details on planning target volume (PTV) size and OAR exposure are shown in table 1. The introduction of INRT decreased the PTV size without reaching statistical significance. There was a consistent decrease in OAR-doses with INRT except for V5 in both lungs and V10 and Dmean in the right lung. Despite the dosimetric advantages, significant differences in favor of INRT could only be found for the spinal cord and thyroid. Conclusion: INRT, in comparison to IFRT, decreases PTV-size and OAR exposure and may help to comply with modern dose constraints [2]. Literature 1. Lancet Oncol. 2021 Feb;22(2):223-234. 2. Blood. 2019 Mar 21;133(12):1384-1385.
P046: Preclinical evaluation of novel repurposed drug combinations in Hodgkin lymphoma
Authors: Mia Lohmann, Iris Buchberger, Anna Beielstein, Başak Kaçar, Julia Mattlener, Marieke Nill, Zhiyuan Shi, Jan-Michel Heger, Christian Pallasch, Roland Ullrich, Sven Borchmann
Journal: HemaSphere (2022)

Although the outcome of patients with Hodgkin lymphoma (HL) is comparably high, it worsens rapidly in relapsed or refractory disease. In the pursuit of improving cancer treatment and finding new therapy options, repurposing drugs has evolved as a promising strategy. This project takes a systematic look at the direct antitumor effect of 12 non-oncological, repurposed drugs in HL that survived initial screening in a broad panel of cell lines. Additionally, we consider their immunological effects and aim to decipher strategies on how to potentially use them in conjunction with immunotherapy. Luciferase toxicity assays in different concentrations were performed with four HL cell lines, narrowing down the list of 12 to the five most toxic agents which were then tested again in three different combinations. The most effective combination was then evaluated in mouse models. To evaluate the influence of the screening survivor drugs on immune response, assays for T-cell activation, macrophage polarization and phagocytosis were conducted. Five compounds, Albendazole (Alb), Auranofin (Aur), Disulfiram (Dis), Fluvastatin (Flu) and Propranolol (Pro) showed markedly elevated in-vitro toxicity. The three combinations Alb+Aur+Dis+Pro, Aur+Dis+Flu+Pro and a combination of all 5 drugs showed synergistic cytotoxicity in HL cell lines. Latter combination clearly reduced tumor growth in mouse models. Except for Doxycycline, which markedly repressed T-cell activation, none of the other tested 11 compounds showed negative effects on either T-cell activation, or macrophage polarization and phagocytosis. On the contrary, Eprosartan (Epro), Metformin (Met), Clofibrate (Clof) and Ornidazole (Orni) increased antibody dependent cellular phagocytosis (ADCP) in in-vitro assays. This project shows that combinations of repurposed, non-oncological drugs at safe doses have a direct cytotoxic effect against HL and a potentially beneficial impact on key immune response mechanisms. Taken together, our results justify further evaluation of combinations of these clinically known drugs with chemotherapy or checkpoint blockade in cases of HL without other treatment options.